More than 7 million Americans work at night, either on permanent shifts or on schedules requiring a rotation of day, evening, and night work. For most of these individuals, complete physiologic adaptation of endogenous circadian rhythms to such inversion of the daily routine fails to occur, even after years of permanent nighttime work. Such physiologic maladaptation to an inverted schedule results in diminished alertness and performance during nighttime work, with associated increases in fatigue-related accidents during nighttime hours. In fact, more than half of all night shift workers report that they are unable to remain awake throughout the night shift, falling asleep at least once per week while on duty. Then, despite nocturnal sleep deprivation, these workers typically experience daytime insomnia. Consequently, these workers suffer from cumulative sleep restriction, further compounding the risk for fatigue-related accidents. In addition to its effects on sleep and alertness, long-term exposure to variable work schedules that include night work is also associated with increased risk of cardiovascular disease, gastrointestinal illness, and reproductive dysfunction in women. Provigil+ (modafinil), a novel wake-promoting therapeutic, recently received FDA approval for treatment of excessive daytime sleepiness (EDS) in patients with narcolepsy. This compound appears to be chemically unrelated to amphetamines and caffeine, and has the potential to be a safe and efficacious alternative to these more traditional stimulants for promoting wakefulness for shiftworkers. Despite modafinil's potential for treating excessive waking sleepiness in normal individuals suffering from acute sleep deprivation and chronic sleep restriction, few studies had investigated its efficacy for promoting wakefulness in acute sleep deprivation conditions. Also, although the inability to remain awake and alert throughout a night of work is one of the greatest safety hazards associated with shift work, the effectiveness of modafinil in preventing the occurrence of involuntary microsleep episodes during night shift work had never been investigated. Finally, although basic science research suggests that modafinil may promote wakefulness by suppressing the buildup of homeostatic sleep drive, no human studies had been done to directly assess the consequence of this possible mechanism of action on subsequent daytime sleep. The purpose of the experiment we started and completed in 1999 was to evaluate the impact of modafinil treatment on waking neurobehavioral alertness and performance and on electroencephalographically (EEG) monitored wakefulness during four nights of simulated night shift work combined with 28 hours of acute sleep deprivation. The effect of modafinil was tested on the following measures: a) computer-administered tests of waking neurobehavioral alertness and performance, b) waking EEG recorded during performance testing, c) actigraphy, d) output of the circadian pacemaker, as marked by endogenous melatonin secretion, and e) full polysomnographic recording of daytime sleep opportunities. From these measures, we are currently determining whether modafinil (200 mg) treatment alleviates excessive waking sleepiness and improved associated neurobehavioral alertness and performance across four consecutive nights of simulated shift work.